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Biomedical subjects

H Reichmann

Publications and source records attributed to H Reichmann.

At least 109 records · Page 6Linked to original sources
PubMed1995

Regional distribution and characterization of nitric oxide synthase activity in the brain of the common marmoset.

The distribution of nitric oxide synthase (NOS) within the brain of the common marmoset, a non-human primate species, was investigated using the [3H]L-citrulline formation assay and Western blot analysis. No hemispheric asymmetry of specific NOS activity was shown. The highest levels of NOS were found in the putamen and caudate nucleus--more than twice those in the cortex and the cerebellum, the brain regions with the lowest activities. The regional distribution pattern was similar to that in the ferret brain and contrasted to that in the mouse and bovine brain. Analysis of NOS catalytic activities in subcellular fractions revealed marked differences in the subcellular localization. Neuronal NOS accounted mainly for the measured catalytic activity in the brain. Differences in the regional distribution pattern of brain NOS activity among species may be indicative of diversities in the functional role of nitric oxide and NOS in mammals.

Amino Acid Oxidoreductases↗
PubMed1995

Inhibition of brain macrophage/microglial respiratory chain enzyme activity in experimental autoimmune encephalomyelitis of the Lewis rat.

We measured the activities of five respiratory chain enzymes in brain macrophages/microglial cells from Lewis rats with experimental autoimmune encephalomyelitis (EAE) and found a significant reduction of the activity of nicotinamide adenine dinucleotide-dehydrogenase (NADH-DH), succinate cytochrome c reductase (SCCR) and succinate dehydrogenase (SDH) when compared with age-matched healthy control animals. The inhibition of NADH-DH (complex I) was specific for EAE, while we also found a reduction of SCCR and SDH activities (complex II) in newborn rats and adjuvant-immunised rats. Activities of NADH cytochrome c reductase (NCCR) and cytochrome c oxidase (COX) were not significantly changed. These observations demonstrate an impairment of brain macrophage/microglial respiratory chain function in central nervous system inflammation.

Animals↗
PubMed1995

Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases.

Successes in classical gene therapies have been achieved by placing a corrected copy of a defective nuclear gene in cells. A similar gene replacement approach for a mutant mitochondrial genome is invariably linked to the use of a yet unavailable mitochondrial transfection vector. Here we show that DNA coupled covalently to a short mitochondrial leader peptide (chimera) can enter mitochondria via the protein import pathway, opening a new way for gene-, antisense-RNA- or antisense-DNA-delivery in molecular therapies. The import behavior of the purified chimera, composed of the amino-terminal leader peptide of the rat ornithine transcarbamylase (OTC) and a double stranded DNA molecule (17 bp or 322 bp), was tested by incubating with coupled and 'energized' rat liver mitochondria in the presence of reticulocyte lysate. The chimera was translocated with a high efficiency into the matrix of mitochondria utilizing the protein import pathway, independent from the size of its passenger DNA.

Amino Acid Sequence↗
PubMed1995

Neurological multisystem manifestation in multiple symmetric lipomatosis: a clinical and electrophysiological study.

Multiple symmetric lipomatosis (MSL) is characterized by a typical neck and shoulder distribution of subcutaneous lipomata and is often associated with polyneuropathy. Occasionally, the central nervous system (CNS) can be involved. Twelve of 14 patients in this retrospective study had clinical or electrophysiological evidence of a predominantly axonal polyneuropathy. Among those were 10 with alcohol abuse, but 2 patients without alcohol abuse also showed clinical or electrophysiological polyneuropathy. Clinical CNS involvement was present in 4 patients. CNS dysfunction was documented by evoked potentials in 8 subjects [prolonged latency or low amplitude of the motor response following cortical magnetic stimulation (4 patients), abnormal visually evoked potentials (4 patients) or somatosensory evoked potentials (SEP) (4 patients)]. These findings were compared to 10 chronic alcoholics without clinical signs of MSL. Five of these showed mild sensory neuropathy. Additionally, 2 also had delayed SEP latencies. Motor evoked potentials were normal in all controls. We propose that the multisystem involvement in MSL demonstrated here cannot be attributed to alcohol abuse alone. Biochemical studies have suggested mitochondrial dysfunction as the basis of the widespread neurological pathology in MSL.

Adult↗
PubMed1995

3.1-kb deletion of mitochondrial DNA in a patient with Kearns-Sayre syndrome.

Mitochondrial DNA (mtDNA) deletions have been found in the majority of patients with chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome. A large number of different mtDNA deletions have been identified. They generally spare the two origins of replication and are frequently flanked by direct or indirect repeats. We have found a 3.1-kb deletion of mtDNA in a patient with Kearns-Sayre syndrome that has some unusual features. First, it encompasses nucleotides 11259 to 14368, a localization that was not described before. Second, the deletion is not flanked by direct or indirect repeats, supporting the view that homologous recombination and slip-replication do not account for all mtDNA deletions.

Base Sequence↗
PubMed1995

Mitochondrial dysfunction in adult-onset myopathies with structural abnormalities.

Three patients with chronic progressive external ophthalmoplegia of adult-onset, generalized muscle atrophy and myalgia are described. Two patients fulfilled the histological criteria for centronuclear myopathy, the third those for fiber-type disproportion. Additionally, typical ragged red fibers were found in all muscle specimens, and several muscle fibers were cytochrome c oxidase negative. NADH and succinate dehydrogenase stains showed increased subsarcolemmal accumulation of mitochondria. To determine whether these findings are coincidental or whether they indicated an additional mitochondrial disorder, all patients were investigated using biochemical analysis of the respiratory chain, molecular genetics, magnetic resonance spectroscopy of quadriceps muscle and ergometry. These tests suggested an additional mitochondrial dysfunction. Mitochondrial dysfunction seems to be more common in this group of myopathies than previously estimated, and may be of importance in the pathogenesis of these disorders.

Adult↗
PubMed1995

Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy.

A woman affected by chronic progressive external ophthalmoplegia and muscle mitochondrial DNA deletion was studied by phosphorus magnetic resonance spectroscopy (31P-MRS) prior to and after 1 and 7 months of treatment with oral lipoic acid. Before treatment a decreased phosphocreatine (PCr) content was found in the occipital lobes, accompanied by normal inorganic phosphate (Pi) level and cytosolic pH. Based on these findings, we found a high cytosolic adenosine diphosphate concentration [ADP] and high relative rate of energy metabolism together with a low phosphorylation potential. Muscle MRS showed an abnormal work-energy cost transfer function and a low rate of PCr recovery during the post-exercise period. All of these findings indicated a deficit of mitochondrial function in both brain and muscle. Treatment with 600 mg lipoic acid daily for 1 month resulted in a 55% increase of brain [PCr], 72% increase of phosphorylation potential, and a decrease of calculated [ADP] and rate of energy metabolism. After 7 months of treatment MRS data and mitochondrial function had improved further. Treatment with lipoate also led to a 64% increase in the initial slope of the work-energy cost transfer function in the working calf muscle and worsened the rate of PCr resynthesis during recovery. The patient reported subjective improvement of general conditions and muscle performance after therapy. Our results indicate that treatment with lipoate caused a relevant increase in levels of energy available in brain and skeletal muscle during exercise.

Adenosine Diphosphate↗
PubMed1995

Metabolic patterns in malignant gliomas.

Changes of mitochondrial and cytoplasm tumor metabolism were studied in malignant gliomas and normal cortex probes in vitro. By spectrophotometric methods marker enzymes of different mitochondrial (whole respiratory chain, citrate acid cycle, fatty oxidation) and cytoplasm (glycolysis, pentose phosphate shunt) metabolic energy pathways were analysed. Generally, the activities of intramitochondrial key enzymes were significantly decreased in gliomas when compared with enzyme activities of normal cortex tissue (p < 0.01). Glycolytic enzymes and a representative of the pentose phosphate shunt were unchanged or increased. Ratios of marker enzymes of the glycolytic pathway (lactate dehydrogenase) and glycose-6-P dehydrogenase revealed a significant difference between glioblastomas (p < 0.05) and grade III (p < 0.05) tumors in comparison to normal astrocytic tissue and astrocytomas WHO grade II. Thus, biochemical analyses allow metabolic grading of gliomas in vitro and may be a useful tool for understanding tumor biology.

Adolescent↗
PubMed1995

Disturbances of cerebrospinal fluid (CSF) circulation--neuropsychiatric symptoms and neuroradiological contribution.

The present study aimed at relating dementia, pseudo-neurasthenic and affective organic brain syndromes to underlying type of CSF flow disorder and to subsequent alteration of anatomy. T2*-weighted magnetic resonance imaging (MRI) in the midsagittal plane permitted an analysis of aqueductal CSF flow phenomena and hydrocephalus-induced elevation, thinning and dorsal impingement of the corpus callosum. Furthermore, the width of the third ventricle was measured on the transverse scout images. 72 patients with communicating hydrocephalus (increased aqueductal CSF pulsations) and 26 patients with aqueductal stenosis (absence of aqueductal flow phenomena) were compared with 22 controls. Dementia and affective disorders were distributed equally among both CSF flow subgroups whereas pseudo-neurasthenic syndromes were observed more frequently in non-communicating hydrocephalus (p < 0.03). Alzheimer-type and multiinfarct dementia syndromes were found more frequently in communicating hydrocephalus whereas non-classifiable dementia showed some predilection for non-communicating hydrocephalus. Callosal height, area and third ventricular width did not predict affective or pseudoneurasthenic disorder whereas third ventricular width (p < 0.01) and callosal area (p < 0.05) discriminated between demented and non-demented patients. Dorsal impingement of the corpus callosum by the falx was a non-specific finding.

Cerebral Aqueduct↗
PubMed1995

The corpus callosum in communicating and noncommunicating hydrocephalus.

To investigate morphological changes in the corpus callosum in hydrocephalus and to correlate them with clinical findings we studied sagittal T2*-weighted cine MR images of 163 patients with hydrocephalus. The height, length and cross-sectional area of the corpus callosum were measured and related to the type of cerebrospinal fluid flow anomaly and to clinical features, especially dementia. With expansion of the lateral ventricles the corpus callosum showed mainly elevation of its body and, to a lesser degree, increase in length. Upward bowing was more pronounced in noncommunicating than in communicating hydrocephalus. Dorsal impingement on the corpus callosum by the free edge of the falx correlated with the height of the corpus callosum. Cross-sectional area did not correlate with either height, length or impingement; it was, however, the strongest anatomical discriminator between demented and nondemented patients. The area of the corpus callosum was significantly smaller in patients with white matter disease. Our findings suggest that, due to its plasticity, the corpus callosum can to some degree resist distortion in hydrocephalus. Dementia, although statistically related to atrophy of the corpus callosum, is possibly more directly related to white matter disease.

Case-Control Studies↗
PubMed1995

Sarcoid myopathy and mitochondrial respiratory chain defects: clinicopathological, biochemical and molecular biological analyses.

We report on a 33-yr-old female patient with myalgia, CK values up to 3500 Ul-1 and proximal weakness. An initial muscle biopsy showed myositis. One year later an enlarged lymph node was investigated and sarcoidosis diagnosed. In a second muscle biopsy inflammatory cells and morphological characteristics of mitochondrial myopathy were found. Biochemical analyses indicated a 50% reduction in complex II activity of the respiratory chain. Due to failure in clinical improvement a third muscle biopsy was performed in 1990 where only 19% of normal complex II activity was present. Southern blot analysis of the mitochondrial genome was normal. Thus for the first time we describe a patient with sarcoid myopathy and a complex II deficiency. Our interpretation is that a pre-existing complex II defect became clinically relevant because of additional sarcoid myopathy.

Adult↗
PubMed1995

Clinical spectrum of the MELAS mutation in a large pedigree.

INTRODUCTION: MELAS is most often due to an mentally transmitted A-G transition mutation of mitochondrial DNA (mtDNA) at position 3243. In this study we report on the clinical spectrum associated with the mutation in the largest family reported so far. PATIENTS AND METHODS: In a family with three MELAS cases we identified 47 persons at risk for the mutation; sufficient data was available on 29. Mitochondrial disease was diagnosed in two of 9 deceased numbers (posthumous molecular analysis in one); 27 surviving family members underwent examination and 25 a molecular analysis of mt DNA from lymphoblasts. Then had a muscle biopsy and two were later autopsied. RESULTS: All 26 cases investigated by molecular analysis showed the mutation at position 3243. The 18 symptomatic patients without stroke-like episodes had sensorineural hearing loss in 15 cases, diabetes in 6, nephropathy in 7, mild myopathy in 4, cardiomyopathy in 2, cerebellar disease in 4 and mental retardation in 2 cases. Eight carriers were asymptomatic. Autopsy showed > 80% mutant mt DNA in all tissues except blood (20%) examined in a MELAS patients, but < 20 mutant mt DNA in all tissues except lever (40%) and kidney (70%) in a patient with hepatopathy, renal failure and diabetes. Histologic and biochemical studies of muscle biopsy were often non-informative. CONCLUSIONS: The mutation of mt DNA at position 3243 causes a multisystem disorder with a variable phenotype due to heteroplasmy. Most carriers are oligosymptomatic with hearing loss and a variety of neurological and internal medical symptoms. Diabetes, cardiomyopathy and renal disease, which is newly reported here for this mutation, are frequent. The blood test is a reliable screening tool in affected families, but is of prognostic value only combined with examination of other tissues.

Biopsy↗
PubMed1995

Degeneration of substantia nigra in chronic Parkinson's disease visualized by transcranial color-coded real-time sonography.

To detect morphologic abnormalities in Parkinson's disease (PD), we examined 30 patients with PD and 30 age- and sex-matched nonparkinsonian controls by transcranial color-coded real-time sonography (TCCS). In 12 severely affected PD patients, the echogenicity of the substantia nigra was distinctly increased. In the remaining 18 PD patients and in all controls, the substantia nigra was poorly visualized or nondetectable by TCCS. The degree of hyperechogenicity of the substantia nigra closely correlated with the severity and duration of PD (p < 0.001). The increased echogenicity of the substantia nigra notably results from nigral gliosis and reflects the stage of degeneration.

Aged↗
PubMed1995

Iron-dependent enzymes in Parkinson's disease.

There is increasing evidence for a mitochondrial disturbance in Parkinson's disease (PD). We present data which favor a defect of complex I of the respiratory chain only in substantia nigra pars compacta. Evidence from literature supports the view that this complex I defect is specific for Parkinson's disease. Questions like feasibility of postmortem biochemical analyses, impairment of the mitochondrial genome, and evidence for the complex I defect as a causative event for PD are discussed in detail. We consider complex I defect to play a most important role in the cell death of dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1995

The TaClo concept: 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a new toxin for dopaminergic neurons.

Due to its structural analogy to the neurotoxin MPTP, "TaClo" (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline), a compound readily originating in vitro from tryptamine ("Ta") and chloral ("Clo"), is discussed as a potential natural inducer of parkinsonian-like symptoms. Its spontaneous formation in man has to be taken into account after application of the drug chloral hydrate or after exposure to the solvent trichloroethylene. This first representative of chloral-derived heterocycles could now indeed be demonstrated to be formed in vivo after application of its putative precursors to rats. In vivo analysis of the nigrostriatal dopamine metabolism, behavioural studies, and histochemical findings as well as a strong inhibition of the complex I of the mitochondrial respiratory chain revealed the neurotoxic potential of TaClo on the dopaminergic system.

Animals↗
PubMed1995

TaClo as a neurotoxic lead: improved synthesis, stereochemical analysis, and inhibition of the mitochondrial respiratory chain.

"TaClo", a highly halogenated tetrahydro-beta-carboline derived from the biogenic amine tryptamine ("Ta") and the synthetic hypnotic chloral ("Clo"), has to be considered as a dopaminergic neurotoxin potentially occurring in vivo. For the preparation of TaClo on a large scale, an improved synthetic pathway was elaborated. The distinct neurotoxic activity of TaClo warrants its intensive study also under stereochemical aspects. For this reason, an analytic device for the separation and stereochemical attribution of its two enantiomers, (R)-TaClo and (S)-TaClo, was developed, based on chromatography on a chiral HPLC phase. Elucidation of the absolute configuration was achieved by CD spectroscopy and confirmed by X-ray crystallography. TaClo exhibits highly selective in vitro inhibition of complex I of the mitochondrial respiratory chain, the required concentrations being much lower than those needed for related halogen-free beta-carbolines or for MPP+ (1-methyl-4-phenyl-pyridinium ion), the active metabolite of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Furthermore, TaClo as a novel lead structure stimulated chemical and neuropharmacological investigations also on related highly halogenated beta-carbolines. Thus, some of the tested compounds--both potential TaClo metabolites and unnatural derivatives--showed even an enhanced inhibition of the mitochondrial respiration in vitro.

Animals↗